Malaria Vaccine Implementation Programme (MVIP) Update to …

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Malaria Vaccine Implementation Programme (MVIP) Update to MPAC

17 October 2018

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Outline

• Brief review of Phase 3 trial results and MVIP

• Mal 076 findings

– 7 year follow-up of children in the large phase 3 trial (Mal 055) at 3 of 11 sites

• Timeline and targets for vaccine introduction

• Update on Framework for Policy Decision

• Data source for safety endpoints

• Funding for last 2 years of MVIP

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RTS,S vaccine efficacy during 48 months follow-up in children first vaccinated at age 5-17 months, 4 doses*

5-17 month age category 4 doses

Clinical malaria 39%

Severe malaria 29%

Severe malaria anaemia 61%

Blood transfusion 29%

Malaria hospitalization 37%

*Efficacy against severe malaria lost without 4th dose.

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Vaccine Impact and Safety

• Potential for high impact moderate/high transmission with 4 doses

– Averted 1000s of cases/1000 children vaccinated over 4 yrs – modelled estimates of 1 death prevented/200 vaccinated

• Safety – Febrile Seizures

• Potential safety signals (no causal relationship established): – Meningitis, cerebral malaria – In setting of very low mortality due to study design, Post-hoc

finding of more deaths among vaccinated vs unvaccinated girls

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Regulatory review

• European Medicines Agency (EMA) issued a positive scientific opinion under article 58

– Applying the same rigorous standards as for medicines to be marketed in the EU

– Stating that the safety profile is acceptable

– Risk-benefit profile favourable

• NRAs from three pilot countries authorized for use in pilot areas

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WHO position and pilot introduction

• Recommended phased introduction in pilot implementations to answer outstanding key questions on

– Feasibility of reaching children with 4 doses, including a 4th dose at 2 years of age

– Safety in the context of routine use, emphasis on meningitis and cerebral malaria

– Impact on mortality (including gender specific) and severe malaria

• Information from Pilot Evaluations will inform WHO policy on the use of RTS,S vaccine across Africa, in 2023

• Vaccine will be piloted in Kenya, Malawi, Ghana

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Components of the MVIP

1. Sub-national introduction by EPI programme through routine systems

2. Rigorous evaluation – Feasibility, safety in routine use, impact

3. GSK-led phase IV observational study

– Includes enrolled cohort of vaccinated & unvaccinated children

– Safety, effectiveness and impact

– Part of GSK risk management plan with EMA

4. PATH-led qualitative assessment/economic analyses

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Malaria-076: 7-year follow-up at 3 of 11 sites Study objectives and design

• Primary objective: describe severe malaria incidence

– Measure rebound after RTS,S 3rd dose or 4th dose

• Secondary objectives:

– Clinical malaria incidence

– Malaria hospitalisation, fatal malaria, cerebral malaria

– SAEs (fatal, malaria related, meningitis, pIMD)

•

8 Presented at MIM, 2018

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Malaria-076: 7-year follow-up at 3 sites Study objectives and design

• Open label, long-term follow-up of children in Mal-055 ‒ 3 study groups (4 dose, 3 dose, control); two age categories

‒ (N =1748)

‒ 3 additional calendar years: Jan 2014 to Dec 2016 ‒ Phase 3 trial: March 2009 through Dec 2013

‒ 3 study sites: Korogwe (Tanzania), Kombewa (Kenya), Nanoro (Burkina Faso)

• Gap between end Malaria-055 and start Malaria-076 with some retrospective data collection prior to prospective : – Nanoro 10 months

– Korogwe 21 months

– Kombewa 24 months

9 Presented at MIM, 2018

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Vaccine efficacy against clinical malaria by follow-up period

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5-17 months

Entire follow-up

Pre dose 4 (Mal055)

Post dose 4 (Mal055)

Post dose 4 + Mal076

Mal076 only

Data for the three sites combined

4 doses 3 doses

7 year: 19% (11, 27) 7 year: 24% (16, 31)

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Vaccine efficacy against severe malaria by follow-up period

(case definition 2)

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5-17 months

Entire follow-up

Pre dose 4 (Mal055)

Post dose 4 (Mal055)

Post dose 4 + Mal076

Mal076 only

Data for the three sites combined

4 doses 3 doses

7 year: 10% (-18, 32) 7 year: 37% (15, 53)

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Vaccine efficacy against severe malaria by follow-up period

(case definition 2)

4 doses 3 doses

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5-17 months

Entire follow-up

Pre dose 4 (Mal055)

Post dose 4 (Mal055)

Post dose 4 + Mal076

Mal076 only

Data for the three sites combined

• Burkina Faso, intensely seasonal: higher incidence clinical malaria compared with controls during last 3 years (Mal 076) in children receiving 3 or 4 doses

• No corresponding higher incidence of severe malaria

7 year: 10% (-18, 32) 7 year: 37% (15, 53)

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Results for severe malaria in study Malaria-076

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The numbers in 5-17 months age category

Group 4 doses RTS,S/AS01 3 doses RTS,S/AS01 Control

N 594 561 593

Endpoint Period n % VE (95% CI) n % VE (95% CI) n

Severe malaria M0-M20 32 50.58 (24.52; 67.65) 57 10.61 (-27.6; 37.38) 65

(case definition 2) M21-SE 31 -2.28 (-68.3; 37.85) 28 6.06 (-56.7; 43.67) 31

Mal-076 7 53.68 (-13.7; 81.13) 11 23.33 (-67.1; 64.82) 15

Total 70 36.69 (14.6; 53.07) 96 10.14 (-18.1; 31.64) 111

Case definition 2: Case definition 1 OR SAE report (within -1 to +3 days of admission) including preferred term of “Malaria”, “P. Falciparum infection” or “Cerebral malaria”

13

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• Deaths during Mal 076

– 1, 2, 2 in 4 dose, 3 dose, control respectively

• Meningitis

– 1 case in control group

• No cases of cerebral malaria (in either age category)

Safety endpoints, 5-17 month age-category

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Interpretation of Mal-076 results

1. Children living in areas with moderate to high perennial malaria transmission who receive 4 doses of RTS,S – Are expected to benefit for at least 7 years after vaccination – Do not have an excess risk of clinical or severe malaria

2. Children living in areas with moderate to high perennial malaria transmission who receive only 3 doses of RTS,S – Are expected to benefit from protection against clinical malaria

for at least 18 months after dose 3 – Do not have excess severe malaria

3. Some settings may experience a limited period of increased risk of clinical malaria – 3 doses, intensely seasonal – Use of other approaches to control malaria should continue

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2018 2019

Jul Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun

Gh

ana

Mal

awi

Current targets for vaccine introduction in 3 pilot countries K

enya

Measles Rubella

Yellow Fever

Yellow Fever

???

IPV

HPV

Original target ???

HPV

Jul? Original target

IPV

Men A

IRB

IRB

IRB

TBC

surveillance

surveillance

surveillance Baseline household survery

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MVIP evaluation partners Ghana Kenya Malawi

Kintampo Health Research Centre (KHRC)

Navrongo Health Research Centre (NHRC)

Research and Development Division (RDD) of Ghana Health Service

University of Ghana School of Public Health Malaria Research Centre, Agogo Presbyterian Hospital

University of Health and Allied Services (UHAS)

Noguchi Memorial Institute for Medical Research

National Foundation for the Centers for Disease Control and Prevention, Inc. (CDC Foundation)

The U.S. Centers for Disease Control and Prevention (CDC)

The KEMRI-Wellcome Trust Research Programme (KWTRP)

The Walter Reed Project (WRP)

The Kenya Medical Research Institute (KEMRI)

The College of Medicine

Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW)

The University of North Carolina Project Malawi (UNCPM)

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Framework for policy decision making

• Framework purpose: describe how MVIP feasibility, safety, and impact data on RTS,S will be used to inform policy

• Joint working group of representatives from SAGE, MPAC, PAG, modelers

– Initial teleconference in July

– Face to face meeting in 3-4 December

– Target presentation to SAGE/MPAC in April 2018 • Preparing background information on inputs to prior policy

decisions

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Data source for safety indicators

Sentinel

hospital

surveillance

Community

mortality

surveillance

Routine PV GSK-led Phase

IV study

Meningitis &

Cerebral Malaria

signal Yes No No Yes

Mortality gender

imbalance No Yes No No

Rare, temporally

related events Yes, but few No Yes Yes

Rebound No No

No

No

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MVIP funding:

• Fundraising for phase 2 beginning now

• Essential to avert a gap in funding between Phase 1 (2017-2020) and Phase 2 (2021-2022)

– Disruption could jeopardize entire programme

– Discussions with GF required prior to year end

– GAVI discussions initiated

– May be difficult for Boards to consider additional funding while vaccinations have not yet begun

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Key milestones achieved since 2017:

– MOH engaged – pilot areas selected, introduction plans developed, introduction activities underway

– Collaboration agreement WHO/PATH/GSK signed

– Advisory bodies set up, convened

– Communication, including launch plans developed

– Training materials developed, adaptation

– Regulatory approval for RTS,S secured

– Vaccine supply ready for shipment

– Master protocol approved, country specific develop

– Improvements in routine pharmacovigilance

– Processes underway for delivery of cold chain equipment, devices and vaccines

– Key staff hired or recruitment underway

– Evaluation partners identified, contracted

– Etc…

Chronology of key milestones in the Malaria Vaccine Implementation

Programme (MVIP) Last updated: September 2018

Cross-cutting Vaccine implementation

Pilot evaluation

2015 Oct: SAGE/MPAC recommend pilot implementation of RTS,S

Dec: WHO issues a call for expression of interest to take part in the MVIP

2016 Jan: First WHO Malaria Vaccine Position Paper published

Apr: Funding proposal submitted to Gavi and Unitaid

Jun: Gavi commits up to $27.5m for Phase 1 contingent on equivalent contributions by others

Jun: Unitaid approves ‘strategic fit’

Sep: Unitaid commits $9.6m for Phase 1 and $3.6m for Phase 2

Sep: PATH provides bridge funding to WHO to start MVIP activities

Nov: Global Fund approves $15m for Phase 1 from its ‘catalytic funds’

Jan: Ministries of Health from 10 countries express interest to take part in the MVIP

Oct-Nov: First MVIP visits to Ghana, Kenya and Malawi to present Programme

Jan: Expert consultation on evaluation design

Jul: First draft of the evaluation protocol

2017 Feb: First full-time staff for MVIP hired at WHO

Apr: Pilot countries announced by RD

June: Unitaid authorizes its contribution for Phase 1

Aug: First meeting of the Strategic Access Task Force

Oct: MVIP Collaboration Agreement between WHO, PATH and GSK signed

Dec: Bilateral funding agreements for Phase 1 signed between WHO and Gavi, Global Fund and Unitaid

Mar: Following confirmation of funding, second MVIP visits to Ghana, Kenya and Malawi to continue planning

Jun: First draft vaccine introduction plan developed by Ghana EPI

Jul: First draft vaccine introduction plan developed by Malawi EPI

Oct: First draft vaccine introduction plan developed by Kenya NVIP

Oct: First meeting of the Programme Advisory Group (PAG) for the MVIP

May: Request for Proposals to identify evaluation partners published by WHO

July: Draft evaluation master protocol submitted to WHO Ethics Review Committee (ERC)

Sept: WHO Contract Review Committee (CRC) endorses shortlist of bidders for further negotiations

Oct: PATH selects its partners for the qualitative Healthcare Utilization study

Oct: Summary submission to EMA (as part of GSK’s RMP) of v6.1 of the evaluation master protocol

Nov: Meeting with prospective evaluation partners at ASHTM to advance negotiations

2018 Jan: First disbursement of MVIP funds to WHO

Apr: First comprehensive public presentation on MVIP at MIM

Apr: Comprehensive MVIP update to SAGE

Jul: Funders approve WHO budget reprogramming request

Feb: Joint regulatory review facilitated by AVAREF

Feb: Generic RTS,S Information, Education and Communication materials made available to country teams

Feb: ERC approves evaluation master protocol

May: Request for Proposals to identify External Monitoring Partners published by WHO

Jul: CRC approves selection of evaluation partners for Ghana and Kenya